1. Field of the Invention
The present invention relates to the field of pharmaceutical chemistry. More particularly, the present invention relates to the discovery of a group of cyclic lipoglycopeptide inhibitors of bacterial signal peptidase useful as antibiotics. The present invention also relates to the production, isolation, and determination of the structure of a family of new lipoglycopeptides from a member of the family Actinomycetes, i.e., Streptomyces sp., and their biological properties related to bacterial signal peptidase inhibition. In addition, the present invention relates to the novel peptide core of these lipoglycopeptides, and a novel process for deacylating the lipoglycopeptides to generate the peptide core, which can be used in the production of further derivatives. These lipoglycopeptide compounds and derivatives of these compounds can be formulated as pharmaceutical compositions that can be used in the treatment of bacterial infections in mammals. Additionally, these compounds can be formulated as compositions that can be used for controlling the growth of disease-causing bacteria on surfaces requiring disinfection.
2. Description of Related Art
Bacterial Infections and Antibiotic Resistance
Bacterial infections remain the leading cause of death worldwide. Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Enterococcus sp., 
Mycoplasma pneumoniae, Escherichia coli, and Enterobacter cloacae are among the major pathogens causing severe infections, which include otitis, sinusitis, pharyngitis, bronchitis, pneumonia, endocarditis, septicemia, and skin and urinary tract infections. These infections are especially problematic among the immune-compromised populations, e.g., AIDS patients.
Signal Peptidases
Most proteins that are translocated across lipid bilayers are synthesized as precursors (preproteins) with an amino-terminal extension known as a signal (or leader) peptide. This signal sequence is involved in guiding the protein into the targeting and translocating pathway by interacting with the membrane and other components of the cellular secretory machinery (Wickner, et al. (1991) Ann. Rev. Biochem. 60, 101-124). The final step in protein translocation and secretion is the release of the mature part of the protein from the membrane, which requires the proteolytic removal of the signal peptide. The proteolytic processing occurs during or shortly after the translocation event and is catalyzed in both prokaryotes and eukaryotes by enzymes known as signal peptidases (SPases). Two major bacterial SPases, SPase I and SPase II, having different cleavage specificities, have been identified. SPase I, also called leader peptidase, is responsible for the processing of the majority of secreted proteins (Dalbey, et al. (1997) Protein Sci. 6, 1129-1138; Tschantz, et al. (1994) Methods Enzymol. 224, 285-301) whereas SPase II, also called prolipoprotein signal peptidase, exclusively processes glyceride-modified lipoproteins (Innis, et al. (1984) Proc. Natl. Acad. Sci.U.S.A. 81, 3708-3712).
Bacterial SPase I possesses unique biochemical and physiological properties. It is one of the essential enzymes in the protein secretion pathway. It is widely distributed in both gram positive and gram negative bacteria, as well as Chlamydia (Cregg, et al. (1996) J. Bacteriol. 178, 5712-5718; Peng, et al. (2001) J. Bacterol. 183, 621-627; Zhang, et al. (1997) Gene 194, 249-255).
Signal peptidase is also present in eukaryotic cells; however, the structure of the enzyme from eukaryotic cells is different from that of the bacterial enzyme. Eukaryotic signal peptidase consists of multiple polypeptides. Bacterial SPase I, unlike eukaryotic signal peptidase, consists of a single polypeptide chain.
Additionally, bacterial SPase I and eukaryotic signal peptidase may have distinctive catalytic mechanisms. Evidence suggests that eukaryotic signal peptidase lacks an apparent catalytic lysine, while bacterial SPase I appears to function as a unique serine protease with a serine-lysine catalytic dyad (Sung, et al. (1992) J. Biol. Chem. 267, 13154-13159; Black, M. T. (1993) J. Bacteriol. 175, 4957-4961; Tschantz, et al. (1993) J. Biol. Chem. 268, 27349-27354). Therefore, bacterial SPase I is a good target for the development of antibacterial agents.
Although there are several classes of antibiotics available on the market, the existing and emerging bacterial resistance and cross-resistance to many of the current antibiotics is a growing problem. Thus, there is a continuing need to identify new and quality targets, and to develop novel antibiotics having novel mechanisms of action to overcome such drug resistance.